Title: Chronic Kidney Disease in Gout in a Managed Care Setting

Transcription

1 Author's response to reviews Title: Chronic Kidney Disease in Gout in a Managed Care Setting Authors: Mahesh J Fuldeore (mahesh.fuldeore@abbott.com) Aylin A Riedel (aylin.reidel@i3innovus.com) Victoria Zarotsky (victoria.zarotsky@i3innovus.com) Bhavik J Pandya (bpandya@tpna.com) Omar Dabbous (odabbous@tpna.com) Eswar Krishnan (lesliel@stanford.edu) Version: 4 Date: 20 May 2011 Author's response to reviews: see over

2 Reviewer: William McCLellan The manuscript 'Chronic Kidney Disease in Gout in a Managed Care Setting' by Fuldeore et al. describes allopurinol dosing and uric acid control among patients with gout and prevalent chronic kidney disease (CKD) in members of a health plan. Data were obtained from claims, laboratory and pharmacy databases. The authors describe the change in allopurinol prescription associated with measured GFR. They report that individuals with CKD were started at lower doses of allopurinol which were decreased with worsening kidney function. Contrrol of uric acid was poor among those with (22.2%) and without (25.6%) CKD, a marginally significant difference (p=0.0409). Comments for authors. Inclusion criteria; page 6 and figure 1. The selection criteria as stated on page 6 and in figure 1 are not entirely consistent. Please clarify in text. The following criterion had previously been omitted and has been added to the Methods section: To qualify patients were also required to be enrolled in the health plan for 365 days during a baseline period and for 365 days during a follow-up period. You should include in this flow diagram the number of individuals with missing uric acid values Patients were not omitted from the study due to missing uric acid values, so this information has not been added to the flow diagram to avoid confusion. However, in the first row of Table 3 we indicate that 2,480 patients (out of the total study sample of 3929) did have lab values. It would be very important to provide a flow diagram of the selection of the study cohort. This has been included as Figure 1. How much time could elapse between claims? The 2 claims could be present at any time from , as indicated in the Methods section: In this study, patients were considered to have gout and were selected for the study if they had a minimum of 2 qualifying claims (as described below) during the time period from January 2002 through December I find the rationale for using the last creatinine measurement during the first 12 months unpersuasive. It is well recognized since Hunsicker et al 1 reported from the MDRD study that GFR slopes are highly variable among individuals with stage 3-4 CKD and for a substantial minority they were flat or positive. Further,

3 everyone had the first creatinine measurement while those individuals having multiple measures may have confounding indications or systematically different health care. A sensitivity analysis using the first measured creatinine would help support your observations. As suggested by the reviewer, we have investigated this issue further. When examining CKD stage using the first serum creatinine measurement during the first 12 months, subject distribution among CKD stages was as follows: No CKD (n=2,383; 60.7%), Stage 2 CKD (n=1,036; 26.4%), Stage 3 CKD (n=359; 9.1%), Stage 4 CKD (n=151; 3.8%). This is similar to the CKD stage distribution obtained using last serum creatinine measurement during the first 12 months, as shown in Table 1 (No CKD n=2,393, Stage 2 CKD n=1,032, Stage 3 CKD n=357, Stage 4 CKD n=147). Subset analysis, page 8. How did you determine that allopurinol therapy was initial and not a delayed continuation? What was the relationship between dose change and creatinine measurement? It seems to me that any changes attributed to awareness of CKD should be done in those with either an antecedent claim for CKD or measured creatinine. We agree with the reviewer, and cannot be certain that the allopurinol therapy was not a delayed continuation. Therefore we have edited this sentence to clarify: In addition, the allopurinol average daily dose was calculated at the time of initial observed dose and at the time of last observation. The relationship between dose change and CKD has been described in the Results section: Only about 14.6% of patients without CKD and 15.6% of patients with CKD had a dose titration. Although there was no significant difference in likelihood of dose titration between all patients with CKD vs. those without CKD (p=0.45), patients with Stage 4 CKD were significantly more likely to have a dose titration compared to patients without CKD (p<0.0001). Table 1 should be describe in text and deleted as a table. Table 1 has been deleted, and the following text was added to the Methods Section: The definition and stages of CKD used for the study are based on staging described by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI TM, as found at with modifications as described below. All patients with egfr 90 were defined as having no CKD (information on kidney damage in the presence of normal egfr was unavailable, so NKF Stage 1 disease was rolled into the no CKD category ). Patients with NKF Stage 2 disease (egfr 60-89), NKF Stage 3 disease (egfr 30-59), or NKF Stage 4 disease (egfr 15-29) were defined as having CKD and assigned to the Stage 2 (mild disease) category, the Stage 3 (moderate disease) category, or the Stage 4 (severe disease) category, respectively. Patients with

4 NKF Stage 5 disease (kidney failure, egfr <15) were rolled into the Stage 4 (severe disease) category, due to small sample size. Results page 10. You state: A total of 3,122 gout patients used allopurinol at least once during the study period (79% of the study population). Since the inclusion criteria included at least gout prescription, this statement is confusing at best. You should clarify. As stated in the Methods section, The first qualifying claim must have been a prescription claim for a gout medication (allopurinol, probenecid, colchicine, and/or sulfinpyrazone). Therefore, some of the patients included in the study had a claim for one of these other gout medications (although they were not used as commonly as allopurinol). Results, page 10. The statement Among the allopurinol users, 1,267 (40.5%) were identified as having CKD, and patients with CKD were more likely to be prescribed allopurinol compared with those who did not have CKD (p <.0001). I am not sure that this is a meaningful statement based on the selection of the study sample which was designed to include individuals with CKD by virtue of the creatinine inclusion criteria. It may well be that the disproportionate numbers of allopurinol prescriptions with a low GFR is confounded by indication (ckeck kidney function in high risk CKD patients treated with a renally dosed drug). We agree with the reviewer s comments and this sentence has been deleted. Results, page 11. I would be very interested in the proportion of subjects with advanced CKD who had a first dose or adjusted dose that reflected renal drug dose adjustment. Are 1st prescribed doses (which are lower on average in CKD subjects) a mix of inappropriate doses for GFR and those consistent with the GFR? As suggested by the reviewer, we investigated this issue further. We compared initial daily dose of allopurinol to the maintenance doses recommended by Hande et al. (Table 4). Our analyses used egfr as a surrogate for creatinine clearance. To summarize, we found that 95.6% of subjects with an egfr 100 or higher had an initial dose that did not exceed the recommended maintenance dose; however, this percentage was only 33.3% for egfr 20-99, and 1.2% for egfr0-19. Consistent with the results presented in Table 3 of the manuscript, our findings do not indicate that initial daily dose of allopurinol is prescribed in a manner that correlates with published guidelines sensitive to renal function. Results, multivariable model of dose change. This analysis would be much more informative if it was restricted to subjects where a creatinine measurement preceded the dose titration. This would strengthen the inference from the model

5 that titration reflected egfr awareness. A bigger issue is that of using absolute change rather than direction of change. One interpretation of your results might be that individuals with CKD, who have higher uric acids and lower doses of alloprinol are more likely to be titrated to a higher, perhaps inappropriate, dose. A polytomous logistic model with increase, no change and decrease as levels of the dependent variable or a regression model with magnitude of dose change as the dependent variable would be interesting in this respect. Dose for allopurinol was only examined at first and last allopurinol fill; titration between intermediate doses (and time of such titration) was not captured. However, the mean time to last serum creatinine measurement in the first 12 months of follow-up was days, while the mean midpoint between date of first allopurinol fill and last allopurinol fill was days. We feel that the time frame for which serum creatinine measurements were captured is appropriate for calculating CKD status that could be tied to allopurinol dose titration. We agree that direction of change would provide additional insight, but have not performed that analysis as part of this study. We have added the following text to the limitations section: (4) The multivariate model examining allopurinol dose change did not distinguish between dose increases or decreases. This would be a valuable direction for future research. References 1. Hunsicker LG, Adler S, Caggiula A, et al. Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int. Jun 1997;51(6): Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1): Reviewer: David Mount This study addresses several issues of considerable importance to clinical nephrology and gout. First it underlines the common co-occurrence of CKD and gout, and that CKD tends to increase baseline sua. Second, it underlines again how few patients with gout CKD or otherwise get to the therapeutic goal of 6.0. Third, it provides an opportunity to review the issue of allopurinol dosing and allopurinol hypersensitivity in CKD and gout, for a renal audience. Finally, this is a timely issue given the evolving but as yet-fully-proven indications for allopurinol in CKD (4).In order of appearance I have the following issues with the manuscript. In the abstract, the sentence The generalizability of these findings.patients doesn t make much sense based on typical clinical practice; what % of patients would have a uric acid measured without a concomitant creatinine? I would suspect and hope that close to zero % of patients with gout don t have a creatinine measured at some point in near proximity to the urate measurment.

6 We agree with the reviewer s comments and this sentence has been deleted. In the Introduction, Gout patients typically. levels is awkward. It seems appropriate to expand on the concept of a uric acid goal; nephrologists are profoundly ignorant of this concept. This has been nicely reviewed by several authorities in the field, e.g. (8). We agree with the reviewer s comments and this sentence has been rephrased to include the concept of a uric acid goal: Gout patients typically exhibit increased levels of serum uric acid, and to manage gout symptoms, it is recommended that serum uric acid levels be lowered to a target of <6 mg/dl. Table 1 is probably unnecessary for a renal audience. In table 4 I was surprised by the initial average allopurinol doses, since patients are ideally started on low dose allopurinol during urate lower therapy to a) avoid provoking a flare and b) avoid exposing patients to higher than necessary allopurinol doses during the initial high risk period for AHS. Along a similar line, how many patients were treated with flare prophylaxis during initiation of allopurinol therapy (1, 13); this ought to be easily extractable, looking for NSAID scripts and/or colchicine. Again, the renal community is not generally aware of the risk of precipitating flares with changing allopurinol up or down. Table 1 has been removed, and this information has been described in the methods sections. 38.6% of subjects had at least 1 pharmacy claim for colchicine in the first 6 months of follow-up. There were no differences by CKD stage. We did not collect data for NSAID prescriptions, so we are not able to provide this information. Further, it may be difficult to determine whether medications were used for prophylaxis or treatment. In the Discussion the statement is made that Allopurinol dosing yet controversial topic. Despite this statement, there is no discussion or acknowledgment of the controversies regarding the actual association between CKD, allopurinol dosing, and AHS. There is NO direct evidence that dose reduction in renal impairment reduces the risk of AHS and the relationship between oxypurinol concentration and AHS remains unproven (10). Furthermore, in a large peer-reviewed case-controlled study of AHS there was no significant difference in allopurinol dose in those patients with AHS and those who tolerated allopurinol (5). Severe hypersensitivity reactions are generally not dose-dependent and do not always correlate with oxypurinol levels (9). AHS is HLA-linked(5, 11), and can possibly be avoided by genetic screening in patients treated with the drug (6). No increase in adverse reactions to allopurinol occurs in patients receiving higher than recommended creatinine clearance-adjusted doses(10, 12); see in particular the recent study from New Zealand (10). Several good reviews of this subject are available, see (2) and (3).

7 We agree that a more balanced discussion is needed. Text has been included in the Discussion to incorporate some of the reviewer s suggested references and address some observations surrounding CKD, dosing, and AHS: Concerns regarding adverse events in particular may influence the aggressiveness of current treatment regimens. Cutaneous adverse reactions to allopurinol occur in approximately 7.7 per 1000 recipients [31], and the incidence of allopurinol hypersensitivity syndrome is about 2-3 times higher among renally impaired patients compared to non renally impaired patients [32]. However, the relationship between adverse events and allopurinol dosing is still not fully understood. Previous studies have shown that patients receiving doses of allopurinol above the recommended dose (as based on the creatinine clearance rate) did not exhibit increased toxicity [33,34]. Other studies have indicated that specific genetic markers may influence the risk of experiencing severe cutaneous adverse reactions following allopurinol treatment [35]. I m not fully in agreement with some of the chosen details in the Conclusions of the manuscript. The central problems with allopurinol use in general are seemingly the seriousness of AHS (with less toxic alternatives), the lack of good safety data for doses >300 mg/day, and the utter ignorance of the medical profession in general that urate-lowering therapy should be titrated to a uric acid goal. This is all compounded by the fact that the median dose of allopurinol to reach goal is ~380 mg/day (7). The urate goal if of course no different in CKD but the lack of knowledge of renal MDs of the concept of urate goals for gout, the overall risk and consequences of AHS, and universal adoption of the Hande algorithm are significant impediments in getting CKD patients to goal with allopurinol. We feel the reviewer has made some good suggestions. We have added the following text to the Conclusion to incorporate some of the points made by the reviewer: Additionally, our results suggest a need to raise awareness among physicians regarding the importance of titrating therapy to reach uric acid goals. 1. Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, and Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 31: , Chao J and Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep 11: , Dalbeth N and Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. Semin Dial 20: , Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincon A, Arroyo D, and Luno J. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 5: , 2010.

8 5. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, and Chen YT. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 102: , Jung JW, Song WJ, Kim YS, Joo KW, Lee KW, Kim SH, Park HW, Chang YS, Cho SH, Min KU, and Kang HR. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol Dial Transplant. 7. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, Garcia-Erauskin G, and Ruiz-Lucea E. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 57: , Perez-Ruiz F and Liote F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum 57: , Puig JG, Casas EA, Ramos TH, Michan AA, and Mateos FA. Plasma oxypurinol concentration in a patient with allopurinol hypersensitivity. J Rheumatol 16: , Stamp LK, O'Donnell JL, Zhang M, James J, Frampton C, Barclay ML, and Chapman PT. Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum 63: , Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, Chucherd P, Konyoung P, Vannaprasaht S, Choonhakarn C, Pisuttimarn P, and Sangviroon A. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 19: , Vazquez-Mellado J, Morales EM, Pacheco-Tena C, and Burgos-Vargas R. Relation between adverse events associated with allopurinol and renal function in patients with gout. Ann Rheum Dis 60: , Wortmann RL, Macdonald PA, Hunt B, and Jackson RL. Effect of prophylaxis on gout flares after the initiation of urate-lowering therapy: analysis of data from three phase III trials. Clin Ther 32: , 2010.